Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus

Introduction ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs) based around its active PC-moiety. To provide proof of concept that ES-62-based SMAs exhibit therapeutic potential in SLE, we have investigated the capacity of two SMAs to protect against nephritis when administered to MRL/Lpr mice after onset of kidney damage. Methods SMAs 11a and 12b were evaluated for their ability to suppress antinuclear antibody (ANA) generation and consequent kidney pathology in MRL/Lpr mice when administered after the onset of proteinuria. Results SMAs 11a and 12b suppressed development of ANA and proteinuria. Protection reflected downregulation of MyD88 expression by kidney cells and this was associated with reduced production of IL-6, a cytokine that exhibits promise as a therapeutic target for this condition. Conclusions SMAs 11a and 12b provide proof of principle that synthetic compounds based on the safe immunomodulatory mechanisms of parasitic worms can exhibit therapeutic potential as a novel class of drugs for SLE, a disease for which current therapies remain inadequate

The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma

Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma

Forces involved with the extraction of casings used in rotary bored piling

Temporary casings are regularly used in the construction of rotary bored piles, to support the pile bore in potentially unstable soils and also to prevent water ingress from loose or water logged soils. The preferred method of removal of casing is by pulling with a crawler crane. However, the magnitude of force generated, particularly during the initial stage of casing extraction, is unknown. This paper describes a series of 50g centrifuge tests designed to model the casing and surrounding soil during extraction by crane. In each test different sized model casings were installed at various embedment depths into a layer of clay overlain by a well-graded sand to provide an array of data. The depth of granular overburden was varied from 60 mm to 120 mm to allow for assessment of the influence of this material on the extraction force whilst the casing sizes modelled 900 mm and 1800 mm prototypes

Diagnosis of lung cancer – improving survival rates

Lung cancer is a major global health burden with high incidence rates but poor long-term survival. Currently, the majority of cases are diagnosed at an advanced stage when surgical resection is not feasible. Screening for lung cancer has been a major focus of research for the last 40 years. Despite this, there is still a lack of evidence to promote its use outside clinical trials. More recently, interest has focused on promoting earlier recognition of symptomatic disease among both the general public and primary care physicians in order to encourage more timely investigation and referral to secondary care. The hope is that this approach may increase the proportion of disease identified in the early tages, allowing more surgical resections and improved five-year survival rates. This article provides an overview of the current evidence base in terms of early diagnosis of lung cancer and provides some examples of innovations to promote this

Assessing the potential of the unexploited Atlantic purple sea urchin, Arbacia punctulata, for the edible market

The global demand for sea urchin as seafood is currently unmet. Despite exploitation of \u3e 40 species across the world, there is a need to identify other candidate species, especially in regions where diversification in production is sought where species are considered native. The Eastern US presents an opportunity to determine the marketability of the currently unexploited Arbacia punctulata which is naturally distributed from Massachusetts and southwards into the Gulf of Mexico. To determine whether A. punctulata had market potential, it was fed one of the following diets to determine whether the gonad tissue (uni) could be manipulated to increase gonad mass and improve gonad color for the market: dried Ulva lactuca, Salmon pellets (Skretting), Tilapia pellets (Ziegler) or an Urchinomics diet designed for sea urchins either fed for 8 weeks or 12 weeks. All of the pelleted feeds (Salmon, Tilapia and Urchinomics) increased gonad mass and altered the color. The colors of the uni were generally darker than the colors that the market would typically prefer but some individuals did exhibit colors which have been classed as acceptable to the European market. This work highlights that further research is worthwhile to assess the market potential of A. punctulata

The unrestricted Skyrme-tensor time-dependent Hartree-Fock and its application to the nuclear response from spherical to triaxial nuclei

The nuclear time-dependent Hartree-Fock model formulated in the three-dimensional space,based on the full Skyrme energy density functional and complemented with the tensor force,is presented for the first time. Full self-consistency is achieved by the model. The application to the isovector giant dipole resonance is discussed in the linear limit, ranging from spherical nuclei (16O, 120Sn) to systems displaying axial or triaxial deformation (24Mg, 28Si, 178Os, 190W, 238U). Particular attention is paid to the spin-dependent terms from the central sector of the functional, recently included together with the tensor. They turn out to be capable of producing a qualitative change on the strength distribution in this channel. The effect on the deformation properties is also discussed. The quantitative effects on the linear response are small and, overall, the giant dipole energy remains unaffected. Calculations are compared to predictions from the (quasi)-particle random phase approximation and experimental data where available, finding good agreement

Microcalcifications Detection using PFCM and ANN

This work presents a method to detect Microcalcifications in Regions of Interest from digitized mammograms. The method is based mainly on the combination of Image Processing, Pattern Recognition and Artificial Intelligence. The Top-Hat transform is a technique based on mathematical morphology operations that, in this work is used to perform contrast enhancement of microcalcifications in the region of interest. In order to find more or less homogeneous regions in the image, we apply a novel image sub-segmentation technique based on Possibilistic Fuzzy c-Means clustering algorithm. From the original region of interest we extract two window-based features, Mean and Deviation Standard, which will be used in a classifier based on a Artificial Neural Network in order to identify microcalcifications. Our results show that the proposed method is a good alternative in the stage of microcalcifications detection, because this stage is an important part of the early Breast Cancer detectio

The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma

Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma

Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation

ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed